Drug resistance in metastatic castration-resistant prostate cancer: an update on the status quo

Yehya, Amani; Ghamlouche, Fatima; Zahwe, Amin; Zeid, Yousef; Wakimian, Kevork; Mukherji, Deborah; Abou-Kheir, Wassim

doi:10.20517/cdr.2022.15

Cited by 15 publications

(11 citation statements)

References 184 publications

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“…In the present special issue, a total of six articles have been qualified and published. The first review published by Yehya et al (2022) shed the light on emerging targeted therapies currently evaluated in clinical trials with promising potential to overcome mCRPC-drug resistance [6] . This review also provides the updated mechanism of action of mCRPC development.…”

Section: Article Descriptionmentioning

confidence: 99%

“…Current systemic treatment options for mCRPC include hormonal therapy, chemotherapy, immunotherapy, radiotherapy, and bone-modifying agents [4] . There are few recently included novel therapies such as PARP inhibitors and immune checkpoint inhibitors including PD-1/PD-L1 and CTLA4 for a subset of mCRPC patients [5] . The special issue of "Drug resistance in metastatic castration-resistant prostate cancer" provides insights into the targets and treatment of mCRPC.…”

Section: Introductionmentioning

confidence: 99%

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New insights for drug resistance in metastatic castration-resistant prostate cancer

Kushwaha¹,

Gupta²

2022

Cancer Drug Resist

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Prostate cancer is the most common cancer and is the second leading cause of cancer-related deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard treatment for advanced-stage prostate cancer; however, this treatment eventually fails, leading to an incurable disease subtype known as metastatic castration-resistant prostate cancer (mCRPC). There are several molecular mechanisms that facilitate the development of mCRPC engaging androgen receptor (AR) growth axis, including AR amplification, gain of function AR mutations, and AR splice variants that are constitutively active and are a foremost factor for mCRPC development. AR-independent mechanisms with exceptionally low or absent AR expression found in cancer cells suppress ADT effectiveness and contribute to aggressive variants, including neuroendocrine differentiation. Several other AR regulatory factors such as epigenetic modification(s), and DNA damage response have been reported during post-ADT exposure and play a crucial role in mCRPC development. Therefore, targeting prostate cancer cells before their progression to mCRPC would improve patient outcomes. This special issue in “Cancer Drug Resistance” focuses on understanding the mechanism(s) and development of mCRPC resistance. This special issue also highlights the therapeutic strategies to combat against resistant subtype. This issue comprehensively reviews the mCRPC and delivers the update in the forum of mCRPC resistance development.

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Section: Article Descriptionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New insights for drug resistance in metastatic castration-resistant prostate cancer

Kushwaha¹,

Gupta²

2022

Cancer Drug Resist

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“…V) Due to plasticity, prostate epithelial cells convert into neuroendocrine cells and induce signals without AR requirement. VI) Tumor microenvironment and signaling alteration of hormones, growth factors, kinases, cytokines, and enzymes are also involved in CRPC (14). In patients with CRPC, resistance to androgen antagonists can also be due to the conversion of these factors in AR agonists, thus supporting PCa instead of suppressing it.…”

Section: Androgens and Prostate Cancermentioning

confidence: 99%

“…The surviving cells transmit androgensensitive PCa to castration-resistant prostate cancer (CRPC), a type of PCa that can continue progression after ADT (13). Nowadays, although multiple drugs for the treatment of patients with CRPC are available and prolong the patients' survival, owing to primary and secondary resistance to these therapies (14), the median survival is only around 42 months (15).…”

Section: Introduction 11 the Prostate Cancermentioning

confidence: 99%

The androgen-thyroid hormone crosstalk in prostate cancer and the clinical implications

Torabinejad

Miro

Barone

et al. 2023

European Thyroid Journal

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There is increasing evidence that thyroid hormones (THs) work in an integrative fashion with androgen receptors (ARs) to regulate gonadal differentiation and reproductive function. Studies reveal that THs have interactions with the AR promoter region and increase AR expression. THs also have a role in the regulation of enzymes involved in the biosynthesis of androgens, such as 5α-reductase, which is essential in the conversion of testosterone into its active form, 5α-dihydrotestosterone. Additionally, the presence of androgen response elements (AREs) in the promoter regions of TH-related genes, such as deiodinases and thyroid hormone receptor isoforms have been identified in some vertebrates, indicating a mutual interaction between THs and ARs. Since the androgen signaling pathway, mediated by ARs, plays a key role in the formation and progression of prostate cancer (PCa), the existence of crosstalk between THs and ARs supports the epidemiologic and experimental evidence indicating a relationship between the high incidence of Prostate Cancer (PCa) and hyperthyroidism. This article aims to review the role of androgen-thyroid hormone crosstalk in PCa and its implication in the clinical management. As life expectancy is growing these days, it can increase the number of patients with PCa and the critical relevance of the disease. In order to gain better knowledge about PCa and to improve the clinical management, it is essential to get better insight into the key factors related to the formation and progression of this cancer.

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“…This overexpression of the AR mRNA is the most frequent alteration in CRPC (up to 81% of cases) [ 25 , 26 ].…”

Section: Castration Resistance Mechanismsmentioning

confidence: 99%

Strategies to Re-Sensitize Castration-Resistant Prostate Cancer to Antiandrogen Therapy

et al. 2023

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Since prostate cancer (PCa) was described as androgen-dependent, the androgen receptor (AR) has become the mainstay of its systemic treatment: androgen deprivation therapy (ADT). Although, through recent years, more potent drugs have been incorporated, this chronic AR signaling inhibition inevitably led the tumor to an incurable phase of castration resistance. However, in the castration-resistant status, PCa cells remain highly dependent on the AR signaling axis, and proof of it is that many men with castration-resistant prostate cancer (CRPC) still respond to newer-generation AR signaling inhibitors (ARSis). Nevertheless, this response is limited in time, and soon, the tumor develops adaptive mechanisms that make it again nonresponsive to these treatments. For this reason, researchers are focused on searching for new alternatives to control these nonresponsive tumors, such as: (1) drugs with a different mechanism of action, (2) combination therapies to boost synergies, and (3) agents or strategies to resensitize tumors to previously addressed targets. Taking advantage of the wide variety of mechanisms that promote persistent or reactivated AR signaling in CRPC, many drugs explore this last interesting behavior. In this article, we will review those strategies and drugs that are able to resensitize cancer cells to previously used treatments through the use of “hinge” treatments with the objective of obtaining an oncological benefit. Some examples are: bipolar androgen therapy (BAT) and drugs such as indomethacin, niclosamide, lapatinib, panobinostat, clomipramine, metformin, and antisense oligonucleotides. All of them have shown, in addition to an inhibitory effect on PCa, the rewarding ability to overcome acquired resistance to antiandrogenic agents in CRPC, resensitizing the tumor cells to previously used ARSis.

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Drug resistance in metastatic castration-resistant prostate cancer: an update on the status quo

Cited by 15 publications

References 184 publications

New insights for drug resistance in metastatic castration-resistant prostate cancer

New insights for drug resistance in metastatic castration-resistant prostate cancer

The androgen-thyroid hormone crosstalk in prostate cancer and the clinical implications

Strategies to Re-Sensitize Castration-Resistant Prostate Cancer to Antiandrogen Therapy

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